Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Mol Ther. 2012 Jun;20(6):1261-9. doi: 10.1038/mt.2012.67. Epub 2012 Apr 10.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. Our laboratory showed that miR-107 expression is reduced and functions as a tumor suppressor gene in HNSCC suggesting the potential application of miR-107 as a novel anticancer therapeutic. In this study, we determined the efficiency and efficacy of cationic lipid nanoparticles to deliver pre-miR-107 (NP/pre-miR-107) in HNSCC cells in vitro and in vivo. NP/pre-miR-107 increased delivery of miR-107 into HNSCC cells by greater than 80,000-fold compared to free pre-miR-107. Levels of known miR-107 targets, protein kinase Cε (PKCε), cyclin-dependent kinase 6 (CDK6), and hypoxia-inducible factor 1-β (HIF1-β), decreased following NP/pre-miR-107 treatment. Clonogenic survival, cell invasion, and cell migration of HNSCC cells was inhibited with NP/pre-miR-107. Moreover, NP/pre-miR-107 reduced the cancer-initiating cell (CIC) population and dampened the expression of the core embryonic stem cell transcription factors, Nanog, Oct3/4, and Sox2. In a preclinical mouse model of HNSCC, systemic administration of NP/pre-miR-107 significantly retarded tumor growth by 45.2% compared to NP/pre-miR-control (P < 0.005, n = 7). Kaplan-Meier analysis showed a survival advantage for the NP/pre-miR-107 treatment group (P = 0.017). Our results demonstrate that cationic lipid nanoparticles are an effective carrier approach to deliver therapeutic miRs to HNSCC.
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，去年诊断出约 60 万例新病例。我们的实验室表明，miR-107 的表达减少，并在 HNSCC 中作为肿瘤抑制基因发挥作用，这表明 miR-107 具有作为新型抗癌治疗药物的应用潜力。在这项研究中，我们确定了阳离子脂质纳米粒在体外和体内递送 pre-miR-107（NP/pre-miR-107）在 HNSCC 细胞中的效率和功效。与游离 pre-miR-107 相比，NP/pre-miR-107 将 miR-107 递送入 HNSCC 细胞的效率提高了 80,000 倍以上。NP/pre-miR-107 处理后，已知的 miR-107 靶标，蛋白激酶 Cε（PKCε），细胞周期蛋白依赖性激酶 6（CDK6）和缺氧诱导因子 1-β（HIF1-β）的水平降低。NP/pre-miR-107 抑制 HNSCC 细胞的集落形成存活，细胞侵袭和细胞迁移。此外，NP/pre-miR-107 减少了癌症起始细胞（CIC）群体，并减弱了核心胚胎干细胞转录因子 Nanog，Oct3/4 和 Sox2 的表达。在 HNSCC 的临床前小鼠模型中，与 NP/pre-miR-对照相比，NP/pre-miR-107 的全身性给药使肿瘤生长显著延迟了 45.2％（P <0.005，n = 7）。Kaplan-Meier 分析显示 NP/pre-miR-107 治疗组具有生存优势（P = 0.017）。我们的结果表明，阳离子脂质纳米粒是将治疗性 miR 递送至 HNSCC 的有效载体方法。
